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Novel System Evaluating In Vivo Pathogenicity of Desmoglein 3-Reactive T Cell Clones Using Murine Pemphigus Vulgaris¹

Hayato Takahashi^*, Masayuki Amagai^*, Takeji Nishikawa^*, Yoshiko Fujii^*, Yutaka Kawakami and Masataka Kuwana^2,

^* Department of Dermatology, Institute for Advanced Medical Research, and Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

Autoreactive T cells are thought to be involved in the pathogenesis of autoimmune diseases, but evidence for their direct pathogenicity is almost lacking. Herein we established a unique system for evaluating the in vivo pathogenicity of desmoglein 3 (Dsg3)-reactive T cells at a clonal level in a mouse model for pemphigus vulgaris (PV), an autoimmune blistering disease induced by anti-Dsg3 autoantibodies. Dsg3-reactive CD4⁺ T cell lines generated in vitro were adoptively transferred into Rag-2^–/– mice with primed B cells derived from Dsg3-immunized Dsg3^–/– mice. Seven of 20 T cell lines induced IgG anti-Dsg3 Ab production and acantholytic blister, a typical disease phenotype, in recipient mice. Comparison of the characteristics between pathogenic and nonpathogenic Dsg3-reactive T cell lines led to the identification of IL-4 and IL-10 as potential factors associated with pathogenicity. Further in vitro analysis showed that IL-4, but not IL-10, promoted IgG anti-Dsg3 Ab production by primed B cells. Additionally, adenoviral expression of soluble IL-4R in vivo suppressed IgG anti-Dsg3 Ab production and the PV phenotype, indicating a pathogenic role of IL-4. This strategy is useful for evaluating the effector function of autoreactive T cells involved in the pathogenesis of various autoimmune diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Health and Labour Sciences Research Grants for Research on Measures for Intractable Diseases from Ministry of Health, Labor and Welfare of Japan, and Keio Gakuji Academic Development Funds.

² Address correspondence and reprint requests to Dr. Masataka Kuwana, Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail address: kuwanam{at}sc.itc.keio.ac.jp

³ Abbreviations used in this paper: Dsg3, desmoglein 3; PV, pemphigus vulgaris; MalBP, maltose-binding protein.

This article has been cited by other articles:

				H. Takahashi, M. Kuwana, and M. Amagai A Single Helper T Cell Clone Is Sufficient to Commit Polyclonal Naive B Cells to Produce Pathogenic IgG in Experimental Pemphigus Vulgaris J. Immunol., February 1, 2009; 182(3): 1740 - 1745. [Abstract] [Full Text] [PDF]